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Biomedical subjects

D Becker

Publications and source records attributed to D Becker.

At least 109 records · Page 6Linked to original sources
PubMed1997

Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth.

Unlike normal melanocytes, primary and metastatic human melanomas express high levels of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) messenger RNA, and expression of these genes is essential in sustaining the proliferation of malignant melanomas in vitro. To determine whether bFGF and FGFR-1 are also required for tumor formation in these cells, liposome-mediated gene transfer was used to deliver episomal vectors containing antisense-oriented bFGF or FGFR-1 cDNAs into human melanomas, grown as subcutaneous tumors in nude mice. The growth of tumors injected with these constructs was completely arrested or the tumors regressed as a result of blocked intratumoral angiogenesis and subsequent necrosis. Thus, inhibition of bFGF/FGFR-1-mediated signaling may open a new avenue for the treatment of advanced-stage melanomas.

Animals↗
PubMed1997

TGF-beta inhibits growth and induces apoptosis in leukemic B cell precursors.

The uncontrolled proliferation of malignant lymphoblasts is the pathobiological hallmark in B cell precursor-ALL (BCP-ALL). Identification of inhibitory growth factors is of great importance for the understanding of growth control of leukemic B cell precursors and the development of novel therapeutic approaches in BCP-ALL. The aim of our study was the analysis of the effect of TGF-beta on cell survival and apoptosis of B cell precursors (BCP) from patients with acute lymphoblastic leukemia in vitro. Experiments were performed in a coculture system with cloned murine fibroblasts, which efficiently block spontaneous ex vivo apoptosis of BCP and thus allows the assessment of cytokine-induced growth inhibition. TGF-beta significantly reduced cell viability of highly purified, FACS isolated CD10+/CD19+ leukemic BCP by a mean of 53% (P = 0.0001). The loss of cell viability was accompanied by a significant increase of apoptosis with a mean of 70% (P = 0.0028). The TGF-beta effect was blocked specifically by a monoclonal anti-TGF-beta antibody. Induction of apoptotic cell death by TGF-beta was not accompanied by reduction of bcl-2 protein expression. TGF-beta transcription was not detected in the leukemic pre-B cell line BLIN-1, but in the murine fibroblasts. The growth inhibitory effect of TGF-beta was not restricted to leukemic BCP. The cytokine also increased apoptosis of normal, highly purified BCP by a mean of 58%. The data identify TGF-beta as a potent growth inhibitory cytokine for leukemic BCP.

Animals↗
PubMed1997

Immunostimulatory effects of platinum compounds: correlation between sensitizing properties in vivo and modulation of receptor-mediated endocytosis in vitro.

The sensitizing properties of different complex salts of platinum were defined in vivo by means of the popliteal lymph node (PLN) assay in mice. Hexa- and tetrachloroplatinates were confirmed to be highly immunogenic, inducing vigorous primary immune responses in the draining PLN following single subcutaneous injections. Flow-cytometric analysis revealed a dramatic increase in the total number of cells expressing proliferating cell nuclear antigen. The majority of these cells were of the T helper phenotype (CD4+) reflecting the T-cell dependence of the PLN response induced by Pt salts such as Na2[PtCl6] or Na2[PtCl4]. In contrast, [Pt(NH3)4]Cl2 failed to elicit a significant increase in PLN cell proliferation when compared with saline-treated controls. The differential immunogenicity of the Pt compounds found in vivo directly correlated with their capacity to modulate mechanisms of receptor-mediated endocytosis in murine Langerhans cells in vitro. The reactivity of Na2[PtCl6] or Na2[PtCl4] resembled that of potent contact sensitizers in this endocytosis assay whereas [Pt(NH3)4]Cl2 proved to be mert. These results suggest that [Pt(NH3)4]Cl2 might be less harmful to humans than hexa- or tetrachloroplatinates. As demonstrated with Pt compounds, monitoring of direct effects of low-molecular-weight chemicals on antigen-presenting dendritic cells in vitro is able to predict their sensitizing potential in vivo.

Adjuvants, Immunologic↗
PubMed1997

Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned?

The aim of this study was to determine the optimal management of patients with propylthiouracil (PTU) hepatotoxicity. A MEDLINE search for English language cases of PTU hepatotoxicity between 1966 and April 1996 was performed, and additional cases were cross-referenced. Twenty-seven cases were selected based on the availability of information on patient management after the onset of hepatotoxicity. Eighty-five percent of the selected cases met this criterion. A detailed summary of the management of two cases of PTU hepatotoxicity at our institutions is also provided. Although most patients recovered once PTU was stopped, seven patients died. Patients with PTU hepatotoxicity who survived were more likely to have received 131I during the course of their illness than those who died (P < 0.03, by Fisher's exact test). In our two patients, hyperbilirubinemia was linearly associated with progressively decreasing T4 levels (r = 0.91; P < 0.001) despite the presence of clinical thyrotoxicosis in one of the patients. These findings demonstrate the need for appropriate clinical evaluation and treatment of thyroid disease during the course of hepatotoxicity. Additionally, we report the first pediatric patient with PTU hepatotoxicity to undergo liver transplantation. The emerging role of liver transplantation in these patients is discussed.

Adolescent↗
PubMed1997

Color Doppler imaging versus phlebography in the diagnosis of deep leg and pelvic vein thrombosis.

The objective of this prospective study was to evaluate the accuracy of color Doppler imaging in comparison to phlebography in diagnosing phlebothrombosis. Five hundred and twenty-six phlebographies (reference method) were compared with 526 color Doppler sonographic examinations. Thrombosis diagnosed with color Doppler imaging showed a sensitivity of 98.0% (400 of 408). In 91.6% (482 of 526) of all examinations the extent of the thrombosis diagnosed with phlebography could also be seen with color Doppler imaging. When the clinical situation is unclear, color Doppler imaging should precede phlebography. Only when findings with ultrasonography are questionable should phlebography definitely be considered.

Adolescent↗
PubMed1997

Psychopathology in dementia.

The purpose of this overview is to describe the psychological and behavioral symptoms of dementia reported in the professional literature in recent years. This subject, a relatively neglected one, is considered in order to focus attention on a number of the symptoms most troublesome to the demented person's surroundings which lead to his/her hospitalization, with all the implications this has on the patients, their families and the community's health budget. To carry out an early and effective intervention, professionals need to define and recognize these symptoms and gain experience in treating them, either by intervention in the environment or by medication. This survey attempts to examine the state of the art in this field, while analyzing the difficulties that emerge in studying it.

Alzheimer Disease↗
PubMed1997

Tc-99m DTPA perfusion scintigraphy and color coded duplex sonography in the evaluation of minimal renal allograft perfusion.

AIM: The clinical impact of perfusion scintigraphy versus color coded Duplex sonography was evaluated, with respect to their potential in assessing minimal allograft perfusion in vitally threatened kidney transplants, i.e. oligoanuric allografts suspected to have either severe rejection or thrombosis of the renal vein or artery. METHODS: From July 1990 to August 1994 the grafts of 15 out of a total of 315 patients were vitally threatened. Technetium-99m DTPA scintigraphy and color coded Duplex sonography were performed in all patients. For scintigraphic evaluation of transplant perfusion analog scans up to 60 min postinjection, and time-activity curves over the first 60 sec after injection of 370-440 MBq Tc-99m diethylenetriaminepentaacetate acid (DTPA) were used and classified by a perfusion score, the time between renal and iliac artery peaks (TDiff) and the washout of the renogram curve. Additionally, evaluation of excretion function and assessment of vascular or urinary leaks were performed. By color coded Duplex sonography the perfusion in all sections of the graft as well as the vascular anastomoses were examined and the maximal blood flow velocity (Vmax) and the resistive index (RI) in the renal artery were determined by means of the pulsed Doppler device. Pathologic-anatomical diagnosis was achieved by either biopsy or post-explant histology in all grafts. RESULTS: Scintigraphy and color coded Duplex sonography could reliably differentiate minimal (8/15) and not perfused (7/15) renal allografts. The results were confirmed either by angiography in digital subtraction technique (DSA) or the clinical follow up. CONCLUSION: In summary, perfusion scintigraphy and color coded Duplex sonography are comparable modalities to assess kidney graft perfusion. In clinical practice scintigraphy and color-coded Doppler sonography can replace digital subtraction angiography in the evaluation of minimal allograft perfusion.

Adult↗
PubMed1996

Changes in voltage activation, Cs+ sensitivity, and ion permeability in H5 mutants of the plant K+ channel KAT1.

KAT1 is a voltage-dependent inward rectifying K+ channel cloned from the higher plant Arabidopsis thaliana [Anderson, J. A., Huprikar, S. S., Kochian, L. V., Lucas, W. J. & Gaber, R. F. (1992) Proc. Natl. Acad. Sci. USA 89, 3736-3740]. It is related to the Shaker superfamily of K+ channels characterized by six transmembrane spanning domains (S1-S6) and a putative pore-forming region between S5 and S6 (H5). The 115 region between Pro-247 and Pro-271 in KAT1 contains 14 additional amino acids when compared with Shaker [Aldrich, R. W. (1993) Nature (London) 362, 107-108]. We studied various point mutations introduced into H5 to determine whether voltage-dependent plant and animal K+ channels share similar pore structures. Through heterologous expression in Xenopus oocytes and voltage-clamp analysis combined with phenotypic analysis involving a potassium transport-defective Saccharomyces cerevisiae strain, we investigated the selectivity filter of the mutants and their susceptibility toward inhibition by cesium and calcium ions. With respect to electrophysiological properties, KAT1 mutants segregated into three groups: (i) wild-type-like channels, (ii) channels modified in selectivity and Cs+ or Ca2+ sensitivity, and (iii) a group that was additionally affected in its voltage dependence. Despite the additional 14 amino acids in H5, this motif in KAT1 is also involved in the formation of the ion-conducting pore because amino acid substitutions at Leu-251, Thr-256, Thr-259, and Thr-260 resulted in functional channels with modified ionic selectivity and inhibition. Creation of Ca2+ sensitivity and an increased susceptibility to Cs+ block through mutations within the narrow pore might indicate that both blockers move deeply into the channel. Furthermore, mutations close to the rim of the pore affecting the half-activation potential (U1/2) indicate that amino acids within the pore either interact with the voltage sensor or ion permeation feeds back on gating.

Amino Acid Sequence↗
PubMed1996

Differential expression of the cyclin-dependent kinase inhibitors p16 and p21 in the human melanocytic system.

To determine whether loss or inactivation of the putative tumor-suppressor gene, p16, represents an initiating or a secondary event in the progression of human melanoma, we evaluated the status of this gene in early and advanced-stage melanomas of sporadic origin. The results of this analysis revealed p16 deletions in 4/6 primary and 6/14 metastatic melanoma cell lines but not in 3/3 metastatic melanoma specimens. Surprisingly, p16 deletions were also detected in 8/8 benign compound nevi and in 1/3 normal human melanocyte isolates. To investigate whether these deletions in benign and malignant stages of the human melanocytic system were specific for p16, we analysed the same specimens and cell lines for expression of p21, another cyclin-dependent kinase inhibitor and potential tumor suppressor. In contrast to p16, expression of p21 was detected in 3/3 melanocytes, in 3/3 benign nevi, and in greater than 50% of malignant melanoma cell lines and specimens. Finally, because of the recently documented inverse relationship between expression of p16 and pRb protein in a variety of tumor cell lines, we analysed some of the p16-positive and negative melanoma cell lines for the presence of pRb protein. The results demonstrated pRb protein in each of these cell lines. Taken together, although this study revealed deletions of the p16 gene in a significant number of sporadic primary and metastatic melanoma cell lines, they were also detected in benign nevus specimens and in some normal human melanocyte isolates. Thus, these findings cast some doubt on the role of this gene as being causal to the onset and progression of human melanoma, in particular, sporadic melanoma.

Base Sequence↗
PubMed1996

Incidence of complications in insulin-dependent diabetes mellitus: a survival analysis.

The authors used 4-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study to investigate the wider applicability of recent research findings that demonstrate an association between glycemic control and insulin-dependent diabetes mellitus (IDDM) complications. EDC subjects participated in clinical examination at baseline (1986-1988) and were followed up every 2 years. Results demonstrated that, during the first 4 years of follow-up, subjects who were in "poor" control (glycosylated hemoglobin (GHb) > or = 11%) at baseline were significantly (p < 0.001) more likely to develop microalbuminuria, proliferative retinopathy, and distal symmetrical polyneuropathy (DSP), compared with subjects who were in "fair" control (GHb < 11%). Subjects who were in poor control were somewhat more likely to develop overt nephropathy (p = 0.08) and renal failure (p = 0.085) during follow-up; however, no associations were observed with either coronary heart disease or lower extremity arterial disease (LEAD). These results confirm the strong association between prior glycemic control and the onset of microalbuminuria, proliferative retinopathy, and DSP observed in the Diabetes Control and Complications Trial study. However, the results of the study suggest weaker associations for the later stages of renal disease, and little relation was seen between glycemic control and LEAD or coronary disease. Other risk factors may be more important for the development of the later complications of IDDM. Further follow-up is necessary in order to rule out type II error.

Adult↗
PubMed1996

Conserved regulatory element involved in the early onset of Hoxb6 gene expression.

We have identified a 338 bp DNA fragment, the lateral plate mesoderm (LPM) enhancer, that is highly conserved between mouse and human. The LPM enhancer directs gene expression into the posterior lateral plate mesoderm and hindgut endoderm at early stages of development. By reporter gene analysis in transgenic mice, we demonstrate that both mouse and human DNA sequences possess similar enhancer activity. The expression patterns of the transgene and Hoxb6 during early stages of mouse development are identical, suggesting that the LPM enhancer is involved in the initial activation of Hoxb6 gene expression in posterior regions of mammalian embryos.

Animals↗
PubMed1996

The limb/LPM enhancer of the murine Hoxb6 gene: reporter gene analysis in transgenic embryos and studies of DNA-protein interactions.

Homeobox genes are expressed in stage-, region-, and tissue-specific patterns during embryonic development of the mouse. In order to study cis-acting regulatory elements of murine homeobox genes, transgenic mouse embryos were generated which contained the LacZ reporter gene under the control of different fragments from the murine Hoxb6 gene. A 2 kb limb/LPM (lateral plate mesoderm) enhancer region was identified which reproduced several aspects of the endogenous Hoxb6 gene expression pattern in the mesenchyme of the developing limb buds and the ventro-lateral body region. Both tissues represent derivatives of the lateral plate mesoderm. In order to describe proteins interacting with specific DNA sequences in the limb/LPM enhancer, electro mobility shift assays were performed using nuclear extracts prepared from embryonic tissues. Several specific DNA-protein complexes could be detected, suggesting that these DNA-protein interactions are important for the regulation of Hoxb6 gene expression.

Animals↗
PubMed1996

Morphological and biochemical changes in neurons: apoptosis versus mitosis.

Apoptosis and mitosis are often thought to share certain morphological similarities and therefore to be regulated by similar sets of enzymes. In this study, the Golgi apparatus and nuclear lamina were examined in PC12 cells and rat superior cervical ganglion neurons undergoing apoptosis in response to withdrawal of nerve growth factor or addition of staurosporine. We found that the Golgi apparatus disperses during apoptosis, without obvious degradation, in a manner similar to that occurring in mitosis. In contrast, the nuclear lamina did not become completely solubilized during apoptosis, as occurs in mitosis, but remained as a distinct structure around the nucleus, although some degradation of nuclear lamins was seen. To assess the integrity of the nuclear envelope, fluorescent probes were introduced into the cytoplasm of live and dying cells. High molecular weight tracers were still excluded from the nuclei of apoptotic cells, demonstrating the continued existence of a functional nuclear barrier. These data suggest, therefore, that cell death is unlikely to occur simply as a result of inappropriate activation of cell cycle enzymes.

Animals↗
PubMed1996

An approach to predictive testing of contact sensitizers in vitro by monitoring their influence on endocytotic mechanisms.

Endocytotic activation of epidermal Langerhans cells (LC) by immunogenic haptens is an early event during development of allergic contact dermatitis. In this work a fast and objective flow-cytometric assay for predictive in vitro testing of contact sensitizers by monitoring their influence on endocytotic mechanisms in murine LC was developed. Epidermal cell suspensions were labelled with a monoclonal antibody directed to MHC class II molecules and pH-sensitive fluorochrome-coupled second-step reagents. For untreated LC a significant quenching of fluorescence intensity by internalization of the MHC-antibody complexes into acidic compartments was noticed. Similar results were obtained in the presence of irritants, the lectin concanavalin A and the phorbol ester phorbol 12-myristate 13-acetate. In contrast stimulation with several well-defined sensitizing compounds resulted in partial conservation of the fluorescence intensity due to the internalization of the labelled complexes into less acidic compartments. Monitoring this modulation of endocytosis is an effective in vitro method to test for properties typical for moderate and strong contact sensitizers. It will help to assess the risk of unknown chemicals to act as haptens and should be useful for restriction of animal experimentation in this field.

Animals↗
PubMed1996

Further insights into transsexualism.

Transsexualism is a challenging entity posing diagnostical, etiological, ethical and moral questions with no general consensus of opinion and a controversial management policy. The present article tries to deal with these questions by drawing a parallel with another psychiatric syndrome in which there is also a disturbance in body image, namely anorexia nervosa. The parallel is at the level of clinical presentation, psychodynamic etiology and their common socioepidemic dimension.

Anorexia Nervosa↗
PubMed1996

Yields of OH in gamma-irradiated DNA as a function of DNA hydration: hole transfer in competition with OH formation.

In this work, we report the yields of hydroxyl radicals, as G values and "destruction constants," in the DNA hydration shell as a function of the level of hydration. Electron spin resonance spectroscopy of gamma-irradiated DNA at low temperatures is employed for detection of the hydroxyl radical. Due to the glassy nature of the DNA hydration layer at low temperature, the hydroxyl radical gives a broad ESR resonance which is easily distinguished from the hydroxyl radical in a polycrystalline ice phase; thus .OH in both glassy and ice regions is quantified. Three regimes of radiological behavior for waters of hydration in DNA are found. For the first approximately 9 waters/nucleotide (which are glassy), no significant amounts of .OH are found, suggesting hole transfer to DNA. The second regime of hydration waters comprises up to about 12 additional glassy waters/nucleotide (gamma = 21). In this regime, substantial amounts of glassy .OH are found, suggesting that only a few holes which escape recombination in spurs charge-transfer to the DNA. In these two glassy regimes no trapped electrons are found, which is in accord with previous work that has reported that all electrons which do not undergo recombination in spurs transfer to DNA. The third regime of hydration water is comprised of bulk (or bulk-like) polycrystalline ice which forms when levels of hydration over 21 waters/nucleotide are reached. These waters form a separate phase from the DNA/glassy-water system, and neither hole nor substantial electron transfer to the DNA occurs; .OH in this ice phase is observed with G values that vary slightly with the amount of water in the ice phase, but which are close to the values found for pure ice.

Animals↗